PHA/ATS Partnership Grant Winner 2006

Todd Bull, MD

University of Colorado “The role of Kaposi’s sarcoma herpesvirus in the development of severe pulmonary hypertension”

Term: January 1, 2006 – December 31, 2007

Summary of Research Project:

The role of Kaposi’s sarcoma herpesvirus in the development of severe pulmonary hypertension

Severe pulmonary arterial hypertension (PAH) is a poorly understood disease with devastating clinical consequences to those afflicted. The disease process of PAH is characterized by an abnormal growth of cells in the pulmonary arteries. The endothelial and smooth muscle cells of the small, pre-capillary pulmonary vasculature proliferate in an uncontrolled fashion, forming the pathologic structure referred to as the “plexiform lesion”. The plexiform lesion manifests a number of characteristics of a cancer including unregulated cell growth. The cells of the plexiform lesion eventually obstruct the pulmonary artery lumen, inhibiting blood flow through the lung. We have recently reported evidence of Human Herpesvirus-8 (HHV-8) infection in the plexiform lesions of patients with idiopathic pulmonary arterial hypertension (IPAH). HHV-8 is a recognized cause of the cancer Kaposi’s sarcoma and is associated with a number of other malignancies. HHV-8 is known to infect endothelial cells and is believed to cause abnormal growth of these cells. In this grant application we propose to investigate mechanisms by which HHV-8 contributes to the development of severe pulmonary hypertension. We have demonstrated the ability of HHV-8 to infect pulmonary microvascular endothelial cells. We will now investigate the effect of this infection on the gene and protein expression of these cells as well as the effect on cell growth and cell apoptosis (programmed cell death). We will also explore a possible connection between HHV-8 infection and alterations in the bone morphogenic protein (BMP) pathway, a pathway recognized to be important in the development of pulmonary hypertension.

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